Polyoxypropylenepolyethylene vitamin E and preparation thereof

ABSTRACT

Disclosed is polyoxypropylenepolyoxyethylene vitamin E, represented by formula (I). It is prepared by subjecting vitamin E to polyethoxylation and then, to polypropoxylation to a proper extent. The vitamin E is of superior anti-oxidation activity with water solubility. The bent chain of the polyoxypropylenepolyoxyethylene vitamin E increases the cross-sectional area of the whole molecule, making it difficult for the molecule to penetrate into the skin. It is very safe to apply to the skin. The polyoxypropylenepolyoxyethylene vitamin E has superb surface activity by forming close bilayer vesicle structures, like phospholipids or dialkyl surfactants, so it can be advantageously used in the cosmetic industry, the food industry and the medical industry. In said formula, R 1  is —(OCH 2 CH 2 ) m — wherein m is an integer of 0 to 150; R 2  is (a) wherein n is an integer of 1 to 200; A is (b) or (c); B is —CH 3  at the 5-, 7- or 8-position of vitamin E; and p is an integer of 1 or 3.

TECHNICAL FIELD

The present invention relates to novel polyoxypropylene-polyoxyethylenevitamin E and a method for preparing the same. More particularly, thepresent invention relates to amphipatic polyoxypropylenepolyoxyethylenevitamin E which is of high surface activity with excellent safety forthe skin. Also, the present invention is concerned with the uses of suchnovel polyoxypropylenepolyoxyethylene vitamin E.

BACKGROUND ART

Generally, surfactants are adsorbed to the interfaces or surfaces ofaqueous solutions to significantly reduce the interfacial tension orsurface tension of the solutions. Depending on the concentration in asolution, surfactants form various types of micelles, which are anassembly of molecules or ions, of which advantage can be taken forvarious purposes.

The lipids which are of surface activity in vivo (bio-surfactants) playa role in regulating the physiological activities of organs and tissues.Bio-surfactants, which can be industrially manufactured, have usefulpurposes in a wide range of industries, including medicines, foods,cosmetics, etc., with classification into dispersants, emulsifiers,solubilizers, foaming agents, anti-foaming agents, polishing agents,slipping agents, surface-treating agents, wetting agents, etc. Inaddition to such function and purpose, ionic property is also aclassification standard for surfactants, leading to ionic and non-ionicsurfactants, and the latter may be further classified into hydrophilicand lipophilic surfactants. While the water solubility of ionicsurfactants is attributed to the presence of ions in hydrophilic groups,non-ionic surfactants exhibit water solubility by virtue of theirhydrogen bond with water.

It is known that the abundance of ionic materials in animal bodiesforces non-ionic materials to be of higher bio-adaptability than ionicmaterials. In fact, non-ionic surfactants are generally used for theproducts which are applied to living bodies.

Hydrophilic non-ionic surfactants do not contain hydrophilic atomicgroups which are ionized, and representative are those which have ahydroxy (—OH) group. Also, hydrophilic non-ionic surfactants may containintramolecular ester bonds (—CO.O—), acid amide bonds (—CO.NH—) and/orether bonds (—O—) although they all are weaker in hydrophilicity than ahydroxy group.

Of hydrophilic non-ionic surfactants, the most widely used and importantare polyethylene glycol condensates which are exemplified by fatty acidpolyethylene glycol condensates (Niosol, Myrj), fatty acid amidepolyethylene glycol condensates, aliphatic alcohol polyethylene glycolcondensates (Leonil, Peregal C), aliphatic amine polyethylene glycolcondensates, aliphatic mercaptane polyethylene glycol condensates (Nyon218), alkylphenyl polyethylene glycol condensates (Igepal), andpolypropylene glycol polyethylene glycol condensates (Pluronics).Besides, various non-ionic surfactants which have complicated structureshave recently been developed and utilized in various purposes,demonstrating their importance.

Generally, as aforementioned, ionic and non-ionic surfactants both areknown to form micelles, which are an assembly of ions or molecules. Asto why they form micelles, there are various differences between ionicsurfactants and non-ionic surfactants. The formation of micelles is oneof the most important properties which surfactants have, and is greatlyaffected by the structures of surfactants. Taking advantage of theseproperties, a great number of surfactants have been developed with theirown purposes. The mechanism in which non-ionic surfactants form micellesin aqueous solutions can be revealed by the research on the surfacetension, light diffusion and interaction with pigment of the micellesand other research. The cause of non-ionic surfactants forming micellesis the property in which the alkyl chains of the surfactant moleculesare extricated from an aqueous phase by the adhesion force of water whenthey reach a critical concentration. In other words, the structure of amicelle is inherent in the structure of the non-ionic surfactantmolecules, specifically in their amphipatic character. These propertiesand structural characteristics of non-ionic surfactants are primarilydetermined by the hydrophobic alkyl structure of the surfactantmolecules. In fact, hydrophobic interactions are the major driving forcefor the formation of micelles or lipid bilayers.

The intensive and thorough research on new surfactants for skin care,repeated by the present inventors, led to the finding that, becausevitamin E was well inserted into the ordered, dense lipid bilayers ofcell membranes to protect the oxidation of the cell membranes, vitamin Eplayed an efficient role as a hydrophobic group if it was applied tosurfactants. As a result of the research, polyoxyethylene vitamin E wasinvented by subjecting vitamin E to addition reaction with ethyleneoxide and patented with its high surface activity, skin soothing andmoisturizing action, and cell protection from harmful active oxygen(Korean Pat. No. 083024, U.S. Pat. No. 5,235,073 and Japanese Pat.Appl'n No. Hei 4-10362). By virtue of its structural characteristics,the polyoxyethylene vitamin E is well absorbed into the interface,showing excellent surface activity. However, there is demanded animprovement in the safety for the skin. Because the hydrophobic, flat,hard chromane ring moiety piles up one by one neatly while the terminalphytyl group has a relatively small sectional area as well as fluidity,the polyoxyethylene vitamin E is too well inserted into the lipidbilayers of cell membranes, causing a problem in safety. This safetyproblem may be overcome by controlling the length of the ethylene oxidechain of the surfactant, that is, by extending the ethylene oxide chain.In this case, however, the polyoxyethylene vitamin E is too hydrophilicto exhibit a desirable surfactant function.

DISCLOSURE OF THE INVENTION

Typically, a surfactant consists of a hydrophobic atomic group and ahydrophilic atomic group with a balanced chemical linkage therebetween.Through intensive study, the present inventor recognized that mostsurfactants are structured to have hydrophobic atomic groups in one endand hydrophilic atomic groups in the other hand, but all are not. Forinstance, the non-ionic surfactant sold under the brand name “Pluronics”has polypropylene oxide as a hydrophobic atomic group, to both sides ofwhich ethylene oxide is repetitively added (T. H. Vaughan, J. Am. OilChemists' Soc. 2p, 240 (1950)), as represented by the following formula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(c)H

wherein a, b and c each is an integer of 20 to 80. Account is needed tobe taken of special examples similar to this (Synthesis of Surfactantsand Application thereof. P4. (1956 Tokyo, Japan). Hydrophilicityprevails over hydrophobicity in ethylene oxide while propylene oxide isa little more hydrophobic than hydrophilic, so their polymers,polyethylene oxide and polypropylene oxide play a role as a hydrophilicatomic group and a hydrophilic atomic group, respectively, within acertain polymerization degree (Daves, J. T., Proc. 2nd Int. Congr.Surface Activity, London 1, 426 (1953)).

As a consequence of the active research which the present inventors havemade on the constituents for cell membranes with the aim of developingsurfactants which are greatly improved in the safety for the skin, itwas perceived that phospholipids have diacyl as a hydrophobic group andexist at a significant quantity in all living microorganisms in additionto being important constituents for all cell membranes. Synthetic ornatural phospholipids are commercially used to form liposomes orvesicles. Another important point which the inventors found out is thatlysophospholipids, each of which contains an acyl group, arecommercially used as emulsifiers by virtue of their superior surfaceactivity to phospholipids themselves (J. L. Harwood and N. L. Russel,Lipids in Plants an Microbes, George Allen and Unwin, London, 1984). Theformation of closed, bilayer liposomes or vesicles can be easilyachieved by phospholipids, but difficultly by lysophospholipids.

Fatty acids, which are components of phospholipids, are safe materialsand widely used in cosmetics, skin ointments, etc. However, fatty acidhave strong toxic influence on cell membranes, so they are permitted tobe used in a very low concentration range; elsewise, they may breakcells occasionally. In phospholipids, fatty acids are linked via esterbonds whereas trace extracellular fatty acids are in a free state. Thus,fatty acids must be esterified at any rate if they exist inintracellular regions including the envelopes (Biosurfactants SurfactantScience Series p27, Vol. 48, 1993, New York, Marcel Dekker Inc.).

From the above fact, it is recognized that surfactants which are ofdiacyl phospholipid structure are inferior in general surface activitysuch as emulsification, but superior in the ability to form liposomes orcell membrane-like vesicles as well as especially in bio-safety tolysophospholipids which are of acyl type.

With the background of the invention in mind, the present inventors haveconducted further research in improving the safety of thepolyoxyethylene vitamin E while maintaining its high surface activityand finally found that, if a hydrophobic moiety is added to the end ofthe hydrophilic moiety of the polyoxyethylene vitamin E, the resultingcompound has a controlled ratio of hydrophilic group to hydrophobicgroup and a different orientation characteristic. In this regard, thehydrophilic polyoxyethylene chain exists between two hydrophobicmoieties, so the extended alkyl chain is converted from an almost linearstate to a bent state, giving rise to an increase in the sectional areaof the surfactant molecule. Consequently, the vitamin E prepared is anon-ionic amphipatic material which is of excellent surface activitywith great improvement in safety for the skin. This material can beprepared by subjecting vitamin E to addition with a hydrophilicpolyethylene oxide chain and a hydrophobic polypropylene oxide chain, insequence, to such an extent that the ratio of the hydrophilic group tothe hydrophobic group is suitable to form vesicles.

Therefore, it is an object of the present invention to provide a novelmodified vitamin E which exhibits high surface activity with reliablesafety for the skin.

It is another object of the present invention to provide a novelmodified vitamin E which is useful in cosmetics, foods, medicines.

It is a further object of the present invention to provide a method forpreparing such a novel modified vitamin E.

It is still a further object of the present invention to provide uses ofsuch a novel modified vitamin E.

In accordance with an aspect of the present invention, there is providednovel polyoxypropylenepolyoxyethylene vitamin E, represented by thefollowing general formula I:

wherein,

R₁ is —(OCH₂CH₂)_(m)— wherein m is an integer of 0 to 150;

R₂ is

 wherein n is an integer of 1 to 200;

A is

 B is —CH₃ at the 5-, 7- or 8-position of vitamin E; and

p is an integer of 1 or 3.

In accordance with another aspect of the present invention, there isprovided a method for preparing the novelPolyoxypropylenepolyoxyethylene vitamin E, in which the vitamin Erepresented by the following general formula II, is subjected toaddition reaction with ethylene oxide, represented by the followingformula III, in the presence of a catalyst and then, with propyleneoxide, represented by the following formula IV, in the presence of acatalyst:

In accordance with a further aspect of the present invention, there isprovided a skin care agent containing the novelpolyoxypropylenepolyoxyethylene vitamin E.

In the present invention, the polyoxypropylenepolyoxyethylene vitamin Ecan be prepared from natural or synthetic vitamin E. In this regard, thevitamin E is subjected to polyethoxylation and then to polypropoxylationin the presence of a catalyst. It may be a Lewis acid catalyst or analkaline catalyst. The polyoxypropylene polyoxyethylene vitamin Eprepared is tested whether it functions well as a surfactant, ananti-oxidant and a skin care agent without harmful effects on the body.In this regard, it is evaluated for anti-oxidation activity by measuringits peroxide value, for foaming ability and foam stability by dynamicfoam testing, for surface tension by the du Nuoy method, and for surfaceactivity by the formation of vesicles. As for the safety in the humanbody, it is confirmed through eye irritation tests and patch tests.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects, features and other advantages of thepresent invention will be more clearly understood from the followingdetailed description taken in conjunction with the accompanyingdrawings, in which:

FIG. 1 is an ¹H-NMR spectrum of synthetic vitamin E (dl α-tocopherol);

FIG. 2 is an ¹H-NMR spectrum of the polyoxypropylenepolyoxyethylenevitamin E (1) prepared in Example I;

FIG. 3 is an ¹H-NMR spectrum of the polyoxypropylenepolyoxyethylenevitamin E (2) prepared in Example II;

FIG. 4 is an ¹H-NMR spectrum of the polyoxypropylenepolyoxyethylenevitamin E (3) prepared in Example III;

FIG. 5 is an ¹H-NMR spectrum of the polyoxypropylenepolyoxyethylenevitamin E (4) prepared in Example IV;

FIG. 6 is an ¹H-NMR spectrum of the polyoxypropylenepolyoxyethylenevitamin E (5) prepared in Example V;

FIG. 7a is an electronic microphotograph showing a vesicle formed by thepolyoxypropylenepolyoxyethylene vitamin E (3) prepared in Example III;and

FIG. 7b is an electronic microphotograph showing a vesicle formed by thepolyoxypropylenepolyoxyethylene vitamin E (4) prepared in Example IV.

BEST MODES FOR CARRYING OUT THE INVENTION

The present invention pertains to novel polyoxypropylenepolyoxyethylenevitamin E. This modified vitamin E is prepared by the sequentialaddition reaction of vitamin E with ethylene oxide and propylene oxidein the presence of an alkaline or Lewis acidic catalyst. When preparingthe polyoxypropylenepolyoxyethylene vitamin E, account must be taken ofvitamin E's being a secondary alcohol with anti-oxidation. Anotheraccount is that the reactive hydroxy group of vitamin is slowly reactedin an early reaction stage owing to the steric hindrance of neighboringCH₃ groups. Accordingly, pertinent selection is required for thequantity of the alkaline or acidic catalyst and the reaction temperatureand pressure to be used.

As the starting material, vitamin E may be a synthetic one, such as dlα-tocopherol, or a natural one, such as that extracted from plant seeds.

Useful examples of the alkaline catalysts include CH₃ONa, NaOH and KOHwhile the Lewis acid catalyst may be selected from BF₃, SnCl₄ and SbCl₅.Based on the weight of the starting material or the polyoxyethylenevitamin E, the catalysts each are used at an amount of 0.02 to 0.8% byweight, but the amount may be changed depending on reaction conditions.

The addition reaction is generally carried out at a temperature of 120to 180° C. and preferably 145 to 160° C. under a pressure of 1.0 to 8.0kg /cm³ and preferably 3.5 to 5.5 kg/cm².

A better understanding of the present invention may be obtained in thelight of the following examples which are set forth to illustrate, butare not to be construed to limit the present invention.

EXAMPLE I Preparation of Polyoxypropylenenpolyoxyethylene Vitamin E (1)

In a 1L double stainless steel autoclave were introduced 112 g (0.26mol) of synthetic vitamin E (dl α-tocopherol) and then, 0.15 g of highlypure methoxy sodium (CH₃ONa). The moisture inside the reactor wasremoved by heating to 70° C. under vacuum of about 720 mmHg for about 20min.

Thereafter, 132 g (3.0 mol) of ethylene oxide was added to the reactorunder pressure and allowed to react at 150-160° C. for about 6 hourswith stirring, so as to give 244 g of a liquid phase of polyoxyethylenevitamin E, which was somewhat dispersed in water. It was subjected toaddition reaction with 35 g (0.6 mol) of propylene oxide for 8 hours at145-155° C. in the presence of 0.1 g of methoxy sodium to give a yellowliquid phase.

After completion of the reaction, the reactor was purged three timeswith gaseous nitrogen to remove unreacted ethylene oxide, propyleneoxide and 1,4-dioxane, a by-product. The reaction mixture was cooled toabout 30° C., followed by adding a trace amount of citric acid toneutralize the alkaline catalyst. It was purified by columnchromatography on Sephadex LH-50 eluting with a chloroform-methanol(1:1, v/v) to afford 265.5 g of polyoxypropylenepolyoxyethylene vitaminE(1) in a liquid phase.

(1) Appearance: a pale yellow liquid at room temperature

(2) Elemental Analysis: as a relative molecular weight of C₅₅H₁₀₂O₁₄

Calculated (%): C 66.94; H 10.34; N: 0.00

Found (%): C 67.16; H 10.82; N: 0.04

(3) Yield: 95.0%

(4) Moles of Added Ethylene oxide: 10 moles on average

(5) Moles of Added Propylene oxide: 2 moles on average

(6) NMR spectrum ¹H-NMR spectra for the synthetic vitamin E and thepolyoxypropylenepolyoxyethylene vitamin E(1) are shown in FIGS. 1 and 2,respectively. As seen, the NMR spectrum of FIG. 1 has a peak for—CH₂CH₂— or —CH₃ read at 1.17-1.3 δ, three peaks for the —CH₃ of thephenyl group at 4.1 δ, and a peak for the —OH group of the trimethylphenol at 4.1 δ. In FIG. 2, the peak at 4.1 δ disappears while peaks forthe H of polyethylene oxide —(CH₂CH₂O)_(m)— and for the H of the

of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)H appear at 3.5-3.8 δ. Also,an H peak of the end —OH of the propylene oxide appears at 3.97 δ and apeak for the —CH₃ of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)— isadditively detected at 1.3 δ.

EXAMPLE II Preparation of Polyoxypropylenenpolyoxyethylene Vitamin E (2)

In a 1L double stainless steel autoclave were introduced 220 g (0.51mol) of synthetic vitamin E (dl α-tocopherol) and then, 0.2 g of highlypure methoxy sodium (CH₃ONa). The moisture inside the reactor wasremoved by heating to 75° C. under vacuum of about 750 mmHg for about 20min.

Thereafter, 130 g (3.0 mol) of ethylene oxide was added to the reactorunder pressure and allowed to react at 145-155° C. for about 6 hourswith stirring, so as to give 348 g of a liquid phase of polyoxyethylenevitamin E, which was somewhat dispersed in water. It was subjected toaddition reaction with 70 g (0.6 mol) of propylene oxide for 8 hours at145-155 C. in the presence of 0.1 g of methoxy sodium to give a yellowliquid phase.

After completion of the reaction, the reactor was purged twice withgaseous nitrogen to remove unreacted ethylene oxide, propylene oxide and1,4-dioxane, a by-product. The reaction mixture was cooled to about 30°C., followed by adding a trace amount of citric acid to neutralize thealkaline catalyst. It was purified by column chromatography on SephadexLH-50 eluting with a chloroform-methanol (1:1, v/v) to afford 405.4 g ofpolyoxypropylenepolyoxyethylene vitamin

E(2) in a liquid phase.

(1) Appearance: a pale yellow liquid at room temperature

(2) Elemental Analysis: as a relative molecular weight of C₄₅H₈₂O₉

Calculated (%): C 70.5; H 10.7; N: 0.00

Found (%): C 71.3; H 11.4; N: 0.03

(3) Yield: 96.5%

(4) Moles of Added Ethylene oxide: 5 moles on average

(5) Moles of Added Propylene oxide: 2 moles on average

(6) NMR spectrum

An ¹H-NMR spectrum for the polyoxypropylenepolyoxyethylene vitamin E(2)is shown in FIG. 3. In this NMR spectrum, when being compared with theNMR spectrum of FIG. 1, the peak for —OH at 4.1 δ disappears while peaksfor the H of polyethylene oxide —(CH₂CH₂O)_(m)— and for the H of the

of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)H appear at 3.5-3.8 δ. Also,an H peak of the end —OH of the propylene oxide appears at 3.97 δ and apeak for the —CH₃ of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)— isadditively detected at 1.3 δ.

The spectrum of FIG. 3 is similar in pattern to, but shorter than thatof FIG. 2 because the moles of the polyoxyethylene and polyoxypropyleneused in this Example were fewer than those of the polyoxyethylene andpolyoxypropylene used in Example I.

EXAMPLE III Preparation of Polyoxypropylenenpolyoxyethylene Vitamin E(3)

In a 2L double stainless steel autoclave were introduced 125 g (0.29mol) of synthetic vitamin E (dl α-tocopherol) and then, 0.2 g of highlypure KOH (99.9%). The moisture inside the reactor was removed by heatingto 77° C. under vacuum of about 740 mmHg for about 30 min.

Thereafter, 300 g (6.8 mol) of ethylene oxide was added to the reactorunder pressure and allowed to react at 160-165 C. for about 6 hours withstirring, so as to give a liquid phase of polyoxyethylene vitamin E,which was well dispersed in water. It was subjected to addition reactionwith 95 g (1.69 mol) of propylene oxide for 8 hours at 155-160° C. inthe presence of 0.15 g of KOH (99.9%) to give a yellow liquid phase.

After completion of the reaction, the reactor was purged three timeswith gaseous nitrogen to remove unreacted ethylene oxide, propyleneoxide and 1,4-dioxane, a by-product. The reaction mixture was cooled toabout 40° C., followed by adding a trace amount of citric acid toneutralize the alkaline catalyst. After unreacted vitamin E was removedwith toluene, the reaction was purified by column chromatography onSephadex LH-50 eluting with a chloroform-methanol (1:1, v/v) to afford505.7 g of polyoxypropylenepolyoxyethylene vitamin E(3) in a liquidphase.

(1) Appearance: a pale yellow semi-solid phase at room temperature

(2) Elemental Analysis: as a relative molecular weight of C₈₅H₁₆₀O₂₇

Calculated (%): C 63.28; H 9.93; N: 0.00

Found (%): C 64.21; H 10.7; N: 0.03

(3) Yield: 97.3%

(4) Moles of Added Ethylene oxide: 20 moles on average

(5) Moles of Added Propylene oxide: 5 moles on average

(6) NMR spectrum

An ¹H-NMR spectrum for the polyoxypropylenepolyoxyethylene vitamin E(3)is shown in FIG. 4. In this NMR spectrum, when being compared with theNMR spectrum of FIG. 1, the peak for —OH at 4.1 δ disappears while peaksfor the H of polyethylene oxide —(CH₂CH₂O)_(m)— and for the H of the

of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)H appear at 3.5-3.8 δ. Also,an H peak of the end —OH of the propylene oxide appears at 3.97 δ and apeak for the —CH₃ of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)— isadditively detected at 1.3 δ.

The spectrum of FIG. 4 is similar in pattern to, but taller than that ofFIG. 2 because the moles of the polyoxyethylene and polyoxypropyleneused in this Example were more than those of the polyoxyethylene andpolyoxypropylene used in Example I.

EXAMPLE IV Preparation of Polyoxypropylenenpolyoxyethylene Vitamin E (4)

in a 2L double stainless steel autoclave were introduced 234 g (0.56mol) of natural vitamin E (α, β, γ, δ-tocopherol mixture), extractedfrom plant seeds, and then, 0.15 g of highly pure methoxy sodium(CH₃ONa). The moisture inside the reactor was removed by heating to 75°C. under vacuum of about 750 mmiHg for about 25 min.

Thereafter, 80 g (1.83 mol) of ethylene oxide was added to the reactorunder pressure and allowed to react at 150-160° C. for about 8 hourswith stirring, so as to give a liquid phase of polyoxyethylene vitaminE, which was little dispersed in water. It was subjected to additionreaction with 36 g (0.62 mol) of propylene oxide for 8 hours at 145-155°C. in the presence of 0.1 g of methoxy sodium (CH₃ONa) to give a yellowliquid phase.

After completion of the reaction, the reactor was purged three timeswith gaseous nitrogen to remove unreacted ethylene oxide, propyleneoxide and 1,4-dioxane, a by-product. The reaction mixture was cooled toabout 30° C., followed by adding a trace amount of citric acid toneutralize the alkaline catalyst. After unreacted vitamin E was removedwith toluene, the reaction was purified by column chromatography onSephadex LH-50 eluting with a chloroform-methanol (1:1, v/v) to afford328.5 g of polyoxypropylenepolyoxyethylene vitamin E(4) in a liquidphase.

(1) Appearance: a pale yellow liquid phase at room temperature

(2) Elemental Analysis: as a relative molecular weight of C₃₈H₆₈O₆

Calculated (%): C 73.55; H 10.97; N: 0.00

Found (%): C 72.53; H 11.4; N: 0.03

(3) Yield: 93.9%

(4) Moles of Added Ethylene oxide: 3 moles on average

(5) Moles of Added Propylene oxide: 1 moles on average

(6) NMR spectrum

An ¹H-NMR spectrum for the polyoxypropylenepolyoxyethylene vitamin E(4)is shown in FIG. 5. In this NMR spectrum, when being compared with theNMR spectrum of FIG. 1, the peak for —OH at 4.1 δ disappears while peaksfor the H of polyethylene oxide —(CH₂CH₂O)_(m)— and for the H of the

of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)H appear at 3.5-3.8 δ. Also,an H peak of the end —OH of the propylene oxide appears at 3.97 δ and apeak for the of polypropylene oxide (CH(CH₃)—CH₂—O)_(n)— is additivelydetected at 1.3 δ.

The spectrum of FIG. 4 is similar in pattern to, but smaller than thatof FIG. 2 because the moles of the polyoxyethylene and polyoxypropyleneused in this Example were fewer than those of the polyoxyethylene andpolyoxypropylene used in Example I.

EXAMPLE V Preparation of polyoxypropylenepolyoxyethylene vitamin E (5)

In a 2L double stainless steel autoclave were introduced 125 g (0.30mol) of synthetic vitamin E (dl α-tocopherol) and then, 0.2 g of highlypure KOH (99.9%). The moisture inside the reactor was removed by heatingto 77° C. under vacuum of about 740 mmHg for about 30 min.

Thereafter, 600 g (13.64 mol) of ethylene oxide was added to the reactorunder pressure and allowed to react at 160-165° C . for about 6 hourswith stirring, so as to give a liquid phase of polyoxyethylene vitaminE, which was well dispersed in water. It was subjected to additionreaction with 175 g (1.64 mol) of propylene oxide for 8 hours at155-160° C. in the presence of 0.15 g of KOH (99.9%) to give a yellowliquid phase.

After completion of the reaction, the reactor was purged three timeswith gaseous nitrogen to remove unreacted ethylene oxide, propyleneoxide and 1,4-dioxane, a by-product. The reaction mixture was cooled toabout 40° C., followed by adding a trace amount of citric acid toneutralize the alkaline catalyst. After unreacted vitamin E was removedwith toluene, the reaction was purified by column chromatography onSephadex LH-50 eluting with a chloroform-methanol (1:1, v/v) to afford893.3 g of polyoxypropylenepolyoxyethylene vitamin E(5) in a liquidphase.

(1) Appearance: a pale yellow solid phase at room temperature

(2) Elemental Analysis: as a relative molecular weight of C₁₅₀H₂₄₈O₅₈

Calculated (%): C 58.5; H 8.1; N: 0.00

Found (%): C 59.2; H 8.0; N: 0.03

(3) Yield: 96.3%

(4) Moles of Added Ethylene oxide: 46 moles on average

(5) Moles of Added Propylene oxide: 10 moles on average

(6) NMR spectrum

An ¹H-NMR spectrum for the polyoxypropylenepolyoxyethylene vitamin E(5)is shown in FIG. 6. in this NMR spectrum, when being compared with theNMR spectrum of FIG. 1, the peak for —OH at 4.1 δ disappears while peaksfor the H of polyethylene oxide —(CH₂CH₂O)_(m)— and for the H of the

of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)H appear at 3.5-3.8 δ. Also,an H peak of the end —OH of the propylene oxide appears at 3.97 δ and apeak for the —CH₃ of polypropylene oxide —(CH(CH₃)—CH₂—O)_(n)— isadditively detected at 1.3 δ.

The spectrum of FIG. 4 is similar in pattern to, but taller than that ofFIG. 2 because the moles of the polyoxyethylene and polyoxypropyleneused in this Example were more than those of the polyoxyethylene andpolyoxypropylene used in Example I.

EXAMPLE VI Preparation of polyoxypropylenepolyoxyethylene vitamin E (6)

The same procedure as in Example III was repeated, except for using 120g (0.29 mol) of natural vitamin E (α, β, γ and δ-tocopherol mixture)instead of synthetic vitamin E, to afford 485 g ofpolyoxypropylenepolyoxyethylene vitamin E (21 EO moles and 5 PO moles onaverage) as a semi-solid phase.

EXAMPLE VII Anti-Oxidation Activity of PolyoxypropylenepolyoxyethyleneVitamin E

An examination was made of the anti-oxidation activity of thepolyoxypropylenepolyoxyethylene vitamin E, using linoleic acid. Thelinoleic acid used was a reagent purchased from Sigma, U.S.A.,comprising linoleic acid 75% and linolenic acid 12.5%.

The polyoxypropylenepolyoxyethylene vitamin E(1) prepared in Example Iwas added at an amount of 0.5% in the linoleic acid while vitamin E,vitamin E acetate, polyoxyethylene (12EO) vitamin E, polyoxyethylene(20EO) sorbitan monostearate (TWEEN-60), and polyoxyethylene (12EO)nonylphenylether (Igepal-CO880) were also used as references. Thesesamples were stored in an incubator maintained at 40° C. At two days andten days after the incubation, a peroxide value was determined for eachsample. In detail, in a 250 ml Erlenmeyer flask was placed 1.0 g of eachof the samples, and 10 ml of chloroform were added to dissolve thesample, after which 15 ml of glacial acetic acid and 1 ml of saturatedpotassium iodide solution were added and a stopper was put in the flask.After being vigorously shaken, the flask was allowed to stand in a darkplace for 5 min. Thereafter, the flask was added with 75 ml of distilledwater and vigorously shaken. Free iodine was titrated with a 0.01 Nsodium thiosulfate solution, using a starch solution as an indicator.The point at which the solution became colorless was regarded as the endpoint. The peroxide value was calculated as follows:${{POV}\left( {{meq}/{kg}} \right)} = \frac{\left( {S - B} \right) \times F}{{Amount}\quad {of}\quad {Sample}\quad (g)}$

S: Amount of 0.01 N sodium thiosulfate solution consumed by sample (ml)

B: Amount of 0.01 N sodium thiosulfate solution consumed in blank testtube (ml)

F: Factor of 0.01 N sodium thiosulfate solution

The results are summarized in Table 1, below.

TABLE 1 Peroxide Values After After Samples 2 days 10 days  1. LinoleicAcid (5° C.) 15.7 16.8  2. Linoleic Acid (40° C.) 30.6 167.2  3.Linoleic acid + vitamin E (0.5%) 21.6 58.9  4. Linoleic acid + Acetateof vitamin E 27.2 123.3  5. Linoleic acid +polyoxypropylenepolyoxyethylene 25.9 118.6 vitamin E(1) (0.5%)  6.Linoleic acid + polyoxypropylenepolyoxyethylene 26.3 120.6 vitamin E(3)(0.5%)  7. Linoleic acid + polyoxypropylenepolyoxyethylene 24.8 108.4vitamin E(4) (0.5%)  8. Linoleic acid + 12EO vitamin E (0.5%) 26.0 124.6 9. Linoleic acid + 20EO sorbitan mono 25.0 126.6 stearate (0.5%) 10.Linoleic acid + 12EO nonylphenylether (0.5%) 28.9 178.5

As apparent from the data of Table 1, thepolyoxypropylenepolyoxyethylene vitamin E (1) prepared in Example I, thepolyoxypropylenepolyoxyethylene vitamin E (3) prepared in Example IIIand the polyoxypropylenepolyoxyethylene vitamin E (4) prepared inExample IV are less potent in anti-oxidation activity than vitamin E, aphysiologically active antioxidant, but show similar anti-oxidationactivity to that of vitamin E acetate, a stable anti-oxidizing vitamin Ederivative, with superiority over polyoxyethylene (12EO),polyoxyethylene (20EO) sorbitan monostearate and polyoxyethylene (12EO)nonylphenylether.

EXAMPLE VIII Surface Activity of polyoxypropylenepolyoxyethylene vitaminE

In order to make an examination of the surface activity of the novelpolyoxypropylenepolyoxyethylene vitamin E, thepolyoxypropylenepolyoxyethylene vitamin E prepared in the Example I toVI was tested for surface tension, foaming ability and foam stability,along with polyoxyethylene (24EO) cholesterol and polyoxyethylene (12EO)vitamin E.

1 Foaming Ability and Foam Stability

The foaming ability and foam stability were determined according to adynamic foam test. First, in a 2 L scaled cylinder with an innerdiameter of 10 cm were charged 40 ml of a 0.1% solution of each samplein water and the solution was stirred at 1,000 rpm 20° C. for 1 min withan agimixer. The height of the foam layer thus formed was regarded asfoaming ability while the ratio of the volume of the foam layer formedimmediately after the stirring to the same maintained at three minutesafter the stirring, was denoted as foam stability. The results are givenin Table 2, below.

TABLE 2 Foaming Ability and Foam Stability Foaming Foam AbilityStability Samples (cc) (%) 24 EO Cholesterol 246 89.6 12 EO vitamin E125 46.5 polyoxypropylenepolyoxyethylene vitamin E(1) 130 43.6polyoxypropylenepolyoxyethylene vitamin E(3) 153 50.3polyoxypropylenepolyoxyethylene vitamin E(5) 251 88.2

The data of Table 2 demonstrate that the polyoxypropylenepolyoxyethylenevitamin E (5) with 46 moles of ethylene oxide and 10 moles of propyleneoxide on average is higher in foaming ability and foam stability thanthe polyoxypropylenepolyoxyethylene vitamin E (1) and shows almost thesame foaming ability and foam stability as the polyoxyethylene (24EO)cholesterol as a reference.

2 Surface Tension

At 20° C., 0.1% solutions of samples in water were measured for surfacetension according to the du Nuoy method with the aid of a surfacetension balance manufactured by Fisher Scientific. The results are givenin Table 3, below.

TABLE 3 Surface Tension in 0.1% Aqueous Solution (20° C.) SurfaceTension Samples (dyne/cm) 24 EO cholesterol 38.4 12 EO vitamin E 56.3polyoxypropylenepolyoxyethylene vitamin E(1) 49.8polyoxypropylenepolyoxyethylene vitamin E(2) 50.5polyoxypropylenepolyoxyethylene vitamin E(3) 45.7polyoxypropylenepolyoxyethylene vitamin E(4) 61.2polyoxypropylenepolyoxyethylene vitamin E(5) 42.5

As shown in Table 3, the polyoxypropylenepolyoxyethylene vitamin E (5)has a surface tension of 42.5 dyne/cm, which is slightly higher thanthat of polyoxyethylene (24EO) cholesterol.

3 Formation of Vesicles

In order to examine another surface action property of thepolyoxypropylenepolyoxyethylene vitamin E, vesicles were formed using0.5% aqueous solutions of the polyoxypropylenepolyoxyethylene vitamin Eprepared in Examples III and V. First, the aqueous solutions maintainedat 25° C. were stirred with a tip type high frequence generator, addedwith an equal volume of a 2% uranyl acetate solution and shaken by hand.Subsequently, the resulting solution was dropwise added on acarbon-coated copper grid with a size of 200 mesh and dried at roomtemperature for about 20 min. Observation was conducted with the aid ofan electronic microscope, manufactured by Philips, operating at 80 KV.The electronic microphotographs are shown in FIG. 7. As seen, there wereformed close globular vesicles with a bilayer structure.

EXAMPLE IX Safety in Living Body

1. Eye Irritation Test

In order to evaluate the safety of the novelpolyoxypropylenepolyoxyethylene vitamin E, a primary eye irritation testwas conducted on rabbits as taught by Draize. Thepolyoxypropylenepolyoxyethylene vitamin E (5) prepared in Example V,polyoxyethylene (12EO) nonylphenylether and polyoxyethylene (20EO)sorbitan monostearate each was diluted with a 10% aqueous glycerinesolution to give a 10% sample solution. This test sample was droppedonto one eye of each of 6 rabbits weighing 2-3 kg while the other eyewas used as a control. 24 hours later, the average scores were recordedaccording to the Draize scoring for ocular lesions. If lesions werepresent, the time was extended; otherwise, observation was ceased.

The results are given in Table 4, below.

TABLE 4 Eye Irritation Test According to Draize Procedure Samples Avg.Values Glycerine (10%) 0.00 polyoxypropylenepolyoxyethylene vitamin E(1)0.12 polyoxypropylenepolyoxyethylene vitamin E(5) 0.10 12 EO vitamin E0.19 12 EO nonylphenylether 0.35 20 EO sorbitan monostearate 0.16

As seen in Table 4, the polyoxypropylenepolyoxyethylene vitamin E (5) isa weaker irritant than the other test samples, that is, polyoxyethylene(20EO) sorbitan monostearate, polyoxyethylene (12EO) vitamin E andpolyoxyethylene (12EO) nonylphenylether and therefore, can be usedsafely in medicines, foods, and cosmetics, such as elemental cosmetics,make-up cosmetics and hair-care cosmetics. The addition amount of thepolyoxypropylenepolyoxyethylene vitamin E according to the presentinvention is dependent on its purposes and the kinds of the materials itis to be used together with, but preferably on the order ofapproximately 0.05 to 60% by weight.

2. Patch Test

In order to confirm non-toxicity of the polyoxypropylenepolyoxyethylenevitamin E according to the present invention, a patch test was conductedon the human body according to the Finn Chamber method. The subjects ofthis test were all females 15-35 years old. A sample material wasdropped onto the brachium of each of the subjects and a dermicel tapewas bonded thereto. The skin irritations were evaluated as a responserate (%) according to an International Contact Dermatitis Research Group(ICDRG) standard after 24 or 48 hour. The results are given in Table 5,below.

TABLE 5 Patch Test Response Rate (%) Samples 24 h 48 hpolyoxypropylenepolyoxyethylene vitamin E(1) 0.3 0.0polyoxypropylenepolyoxyethylene vitamin E(5) 0.5 0.0 20 EO sorbitanmonostearate 0.6 0.0 12 EO vitamin E 1.6 0.8 12 EO nonylphenylether 2.42.0

The data shown in Table 5 demonstrate thepolyoxypropylenepolyoxyethylene vitamin E has no irritations on the skinand is safer to apply to the skin than the controls, polyoxyethylene(20EO) sorbitan monostearate, polyoxyethylene vitamin E andpolyoxyethylene (12EO) nonylphenyl ether.

INDUSTRIAL APPLICABILITY

As described hereinbefore, the polyoxypropylenepolyoxyethylene vitamin Eof the present invention, which can be prepared by the two-step additionreaction of the antioxidant and physiological active vitamin E withethylene oxide and then with hydrophobic propylene oxide to a properextent, is of superior anti-oxidation activity with water solubility.The bent chain of the polyoxypropylenepolyoxyethylene vitamin Eincreases the cross sectional area of the whole molecule, making itdifficult for the molecule to penetrate into the skin. Therefore, it isvery safe to apply on the skin. In addition, thepolyoxypropylenepolyoxyethylene vitamin E has superb surface activity byforming close bilayer vesicle structures, like phospholipids or dialkylsurfactants, so it can be advantageously used in the cosmetic industry,the food industry and the medical industry.

The present invention has been described in an illustrative manner, andit is to be understood the terminology used is intended to be in thenature of description rather than of limitation. Many modifications andvariations of the present invention are possible in light of the aboveteachings. Therefore, it is to be understood that within the scope ofthe appended claims, the invention may be practiced otherwise than asspecifically described.

What is claimed is:
 1. Polyoxypropylenepolyoxyethylene vitamin E,represented by the following general formula I:

wherein, R₁ is —(OCH₂CH₂)_(m)— wherein m is an integer of 0 to 150; R₂is

 wherein n is an integer of 1 to 200; A is

B is —CH₃ at the 5-, 7- or 8-position of vitamin E; and p is an integerof 1 or
 3. 2. A method for preparing polyoxypropylenepolyoxyethylenevitamin E, represented by the following general formula I:

wherein, R₁ is —(OCH₂CH₂)_(m)— wherein m is an integer of 0 to 150; R₂is

wherein n is an integer of 1 to 200; A is

B is —CH₃ at the 5-, 7- or 8-position of vitamin E; and p is an integerof 1 or 3, in which the vitamin E represented by the following generalformula II:

wherein A, B and p each are as defined above, is subjected to additionreaction with ethylene oxide, represented by the following formula III:

in the presence of a catalyst and then, with propylene oxide,represented by the following formula IV;

in the presence of a catalyst.
 3. A method as set forth in claim 2,wherein the vitamin E is selected from the group consisting of syntheticvitamin E, natural vitamin E and ester compounds thereof.
 4. A method asset forth in claim 3, wherein the synthetic vitamin E is selected fromthe group consisting of dl-α tocopherol, dl-β tocopherol, dl-γtocopherol and dl-δ tocopherol.
 5. A method as set forth in claim 3,wherein the vitamin E is vitamin E acetate or vitamin E succinate.
 6. Amethod as set forth in claim 2, wherein thepolyoxypropylenepolyokyethylene vitamin E has suitable surface activityby selecting m and n from integers ranging from 0 to 150 and from 1 to200, respectively.
 7. A method as set forth in claim 2, wherein thecatalyst is an alkaline catalyst selected from CH₃ONa, NaOH and KOH or aLewis acid catalyst selected from BF₃, SnCl₄ and SbCl₅ and is used at anamount of 0.02 to 0.8% by weight in the polyethoxylation step and thepolypropoxylation step, each.
 8. A method as set forth in claim 2,wherein the addition reaction is carried out at a temperature of 135 to170° C.
 9. A method as set forth in claim 2, wherein the additionreaction is carried out under a pressure of 3.5 to 5.5 kg/cm².
 10. Asurfactant, comprising the polyoxypropylenepolyoxyethylene vitamin E ofclaim 1 as an active ingredient.
 11. An anti-oxidant, comprising thepolyoxypropylenepolyoxyethylene vitamin E of claim 1 as an activeingredient.
 12. A humectant, comprising thepolyoxypropylenepolyoxyethylene vitamin E of claim 1 as an activeingredient.